The present invention relates to nutritional supplements for individuals suffering from cerebral metabolic insufficiencies and methods of treating disorders indicated by cerebral metabolic insufficiencies.
During normal operation of the catabolic process, energy is harvested and subsequently stored in a readily available form, namely, the phosphate bonds of adenosine triphosphate (xe2x80x9cATPxe2x80x9d). When energy is required for anabolic processes, a phosphate bond of ATP is broken to yield energy for driving anabolic reactions and adenosine diphosphate (xe2x80x9cADPxe2x80x9d) is regenerated. The process of catabolism involves the breakdown of proteins, polysaccharides, and lipids. Proteins are broken into smaller peptides and constituent amino acids, polysaccharides and disaccharides are broken down into their monosaccharide constituents, and lipids are broken down into glycerol and the fatty acid constituents. These compounds are further broken down into even smaller compounds, principally, two-carbon acetyl groups.
The two-carbon acetyl group, an essential component in the catabolic process, is introduced into the Krebs tricarboxylic acid cycle (xe2x80x9cKrebs cyclexe2x80x9d) via acetyl coenzyme A. The acetyl group serves as a carbon source for the final stages of catabolism. The Krebs cycle and an accompanying electron transport system involve a series of enzymatically controlled reactions which enable complete oxidation of the two-carbon acetyl group to form carbon dioxide and water. As shown in FIG. 1, acetyl groups are introduced into the Krebs cycle by bonding to oxaloacetic acid to form citric acid. During subsequent steps of the Krebs cycle, citric acid is converted into aconitic acid and then isocitric acid or, alternatively, it is converted directly into isocitric acid. As isocitric acid is converted into ketoglutaric acid, one carbon atom is completely oxidized to carbon dioxide. As ketoglutaric acid is converted into succinic acid, a second carbon atom is completely oxidized to carbon dioxide. During the remaining steps, succinic acid is converted into fumaric acid, fumaric acid is converted into malic acid, and malic acid is converted into oxaloacetic acid. Each complete turn of the Krebs cycle harvests the energy of the acetyl group to yield one molecule of ATP, three molecules of nicotinamide adenine dinucleotide (xe2x80x9cNADHxe2x80x9d), and one molecule of flavin adenine dinucleotide FADH2. The NADH and FADH2 are subsequently used as electron donors in the electron transport system to yield additional molecules of ATP.
The Krebs cycle and the accompanying electron transport system occur in the mitochondria, which are present in different types of cells in varying numbers depending upon the cellular energy requirements. For example, neuronal and muscle cells have high numbers of mitochondria because they have extremely high energy requirements. Because of their high energy requirements, these types of cells are particularly vulnerable to disorders or conditions associated with a breakdown of the catabolic pathways or otherwise defective intracellular energy metabolism. Exemplary disorders or conditions include Alzheimer""s Disease (xe2x80x9cADxe2x80x9d), Parkinson""s Disease (xe2x80x9cPDxe2x80x9d), Huntington""s Disease (xe2x80x9cHDxe2x80x9d), and other neurodegenerative disorders (Beal et al., xe2x80x9cDo Defects in Mitochondrial Energy Metabolism Underlie the Pathology of Neurodegenerative Diseases?,xe2x80x9d Trends Neurosci. 16(4):125-131 (1993); Jenkins et al., xe2x80x9cEvidence for Impairment of Energy Metabolism in vivo in Huntington""s Disease Using Localized 1H NMR Spectroscopy,xe2x80x9d Neurol. 43:2689-2695 (1993)).
AD is one of the most commnon causes of disabling dementia in humans. Because AD is a progressive, degenerative illness, it affects not only the patient, but also their families and caregivers. In early stages of AD, activities of daily living (xe2x80x9cADLsxe2x80x9d) are only minimally affected by cognitive or functional impairment, which may often be a first clinical sign of the disease (Small et al., xe2x80x9cDiagnosis and Treatment of Alzheimer Disease and Related Disorders,xe2x80x9d Consensus Statement of the American Association for Geriatric Psychiatry, the Alzheimer""s Association, and the American Geriatrics Society, JAMA 278:1363-1371 (1997)). As AD progresses, the patients"" ability to perform ADLs diminishes and they become increasingly more dependent upon caregivers and other family members (see Galasko et al., xe2x80x9cAn Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer""s Disease,xe2x80x9d Alzheimer Dis. Assoc. Disord. 11 (Suppl. 2):S33-S39 (1997)).
PD is widely considered to be the result of degradation of the pre-synaptic dopaminergic neurons in the brain, with a subsequent decrease in the amount of the neurotransmitter dopamine that is being released. Inadequate dopamine release, therefore, leads to the onset of voluntary muscle control disturbances symptomatic of PD. The motor dysfunction symptoms of PD have been treated in the past using dopamine receptor agonists, monoamine oxidase binding inhibitors, tricyclic antidepressants, anticholinergics, and histamine H1-antagonists. Unfortunately, the main pathologic event, degeneration of the cells in substantia nigra, is not helped by such treatments. The disease continues to progress and, frequently after a certain length of time, dopamine replacement treatment will lose its effectiveness. In addition to motor dysfunction, however, PD is also characterized by neuropsychiatric disorders or symptoms. These include apathy-amotivation, depression, and dementia. PD patients with dementia have been reported to respond less well to standard L-dopa therapy. Moreover, these treatments have little or no benefit with respect to the neuropsychiatric symptoms.
HD is a familial neurodegenerative disorder that afflicts about 1/10,000 individuals (Martin et al., xe2x80x9cHuntington""s Disease: Pathogenesis and Management,xe2x80x9d N. Engl. J. Med. 315:1267-1276 (1986); Gusella, xe2x80x9cHuntington""s Disease,xe2x80x9d Adv. Hum. Genet. 20:125-151 (1991)). It is inherited in an autosomal dominant manner and is characterized by choreiform movements, dementia, and cognitive decline. The disorder usually has a mid-life onset, between the ages of 30 to 50 years, but may in some cases begin very early or much later in life. The symptoms are progressive and death typically ensues 10 to 20 years after onset, most often as the result of secondary complications of the movement disorder. The major site of pathology in HD is the striatum, where up to 90% of the neurons may be depleted. The impaired cognitive functions and eventual dementia may be due either to the loss of cortical neurons or to the disruption of normal activity in the cognitive portions of the basal ganglia. The characteristic chorea is believed to be caused by the neuronal loss in the striatum, although a reduction in subthalamic nucleus activity may also contribute.
Glutamate-induced neuronal cell death is believed to contribute to HD. Glutamate is the principal excitatory transmitter in the brain. It excites virtually all central neurons and is present in the nerve terminals in extremely high concentrations (10xe2x88x923M). Glutamate receptors are divided into four types (named after their model agonists): kainate receptors, N-methyl-D-aspartate (xe2x80x9cNMDAxe2x80x9d) receptors, xcex1-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (xe2x80x9cAMPAxe2x80x9d) receptors, and metabolotrophic receptors. Many normal synaptic transmission events involve glutamate release. However, glutamate can also induce neurotoxicity and neuronal death at high levels (Choi, xe2x80x9cGlutamate Neurotoxicity and Diseases of the Nervous System,xe2x80x9d Neuron, 1:623-634 (1988)). The mechanism of cell death occurs primarily by the persistent action of glutamate on the NMDA receptors. These toxic changes produced by glutamate, called glutamate excitotoxicity, are believed to be the cause of cell damage and death after acute brain injury such as stroke or excessive convulsions. It has been suggested that excitotoxicity may be involved in brain ischemia, AD, and HD (Greenamyre et al., xe2x80x9cAlterations in L-glutamate Binding in Alzheimer""s and Huntington""s Diseases,xe2x80x9d Science, 227:1496-1499 (1985); Choi, xe2x80x9cGlutamate Neurotoxicity and Diseases of the Nervous System,xe2x80x9d Neuron, 1:623-634 (1988)).
The administration of agents that improve energy metabolism, and possibly prevent cell death, has been suggested for the treatment of disorders characterized by energy-deficient cells (Beal et al., xe2x80x9cDo Defects in Mitochondrial Energy Metabolism Underlie the Pathology of Neurodegenerative Diseases?,xe2x80x9d Trends Neurosci. 16(4):125-131 (1993)). One approach to augmenting the energy level of energy-deficient cells (i.e., as a result of hypoxia or hypoglycemia) involves the administration of pyruvate, which is later converted to acetate during normal metabolism. According to U.S. Pat. No. 5,395,822 to Izumi et al. (xe2x80x9cIzumixe2x80x9d), the administration of pyruvate to a patient before or after an ischemic event (i.e., which produces a state of hypoxia or hypoglycemia) is sufficient to prevent neuronal degradation that normally is associated with the ischemic event. Izumi also identified the administration of glucose prior to an ischemic event as undesirable, because its administration resulted in lactic acidosis, which is a factor contributing to brain damage.
An approach for the treatment of AD includes the administration of NADH or nicotinamide adenine dinucleotide phosphate (xe2x80x9cNADPHxe2x80x9d), or the salts thereof. The administration of NADH or NADPH is described in U.S. Pat. No. 5,444,053 to Birkmayer, which discloses the use of salts formed with various acids including, among others, malic acid, succinic acid, and acetic acid. Similar approaches to treating PD using NADH and NADPH are described in U.S. Pat. Nos. 5,019,561 and 4,970,200, both to Birkmayer.
The present invention is directed toward overcoming these above-noted deficiencies in treating conditions associated with a breakdown of the catabolic pathways or otherwise defective intracellular energy metabolism.
The present invention relates to a pharmaceutical composition which includes a sugar and a Krebs cycle intermediate or salt thereof, or a precursor of a Krebs cycle intermediate. Krebs cycle intermediates include citric acid, aconitic acid, isocitric acid, xcex1-ketoglutaric, succinic acid, fumaric acid, malic acid, oxaloacetic acid, and mixtures thereof. Precursors of Krebs cycle intermediates are compounds which, upon administration to a subject, are converted by the body to form a Krebs cycle intermediate.
The present invention also relates to a method of treating impaired mitochondrial function. The method includes administering a pharmaceutical composition of the present invention to a subject having a disorder involving impaired mitochondrial function under conditions effective to improve mitochondrial function.
The present invention further relates to a method of improving cerebral function in an individual having impaired cerebral metabolism. This method includes administering a pharmaceutical composition of the present invention to a subject having impaired cerebral metabolism under conditions effective to improve cerebral function.
The pharmaceutical compositions of the present invention are particularly desirable for the prophylaxis or treatment of disorders associated with impaired mitochondrial function. Disorders that can be treated include conditions or diseases characterized by a decreased level of oxidative metabolism, such as conditions or diseases of the nervous system, conditions or diseases of other parts of the body (e.g., cardiovascular disorders, musculoskeletal disorders, etc.), and conditions or diseases of the body as a whole. The pharmaceutical composition is particularly desirable for use in treating nervous system disorders that are indicated by symptoms of dementia. Upon administration of the pharmaceutical compositions of the present invention, it is possible to reduce the severity of dementia through enhancing cerebral cellular metabolism (i.e., improving mitochondrial function in cerebellar tissues). Thus, the pharmaceutical compositions are particularly useful as a prophylactic for delaying the onset of dementia or as a treatment for delaying the progression of dementia associated with various nervous system disorders. The pharmaceutical compositions are also useful for ameliorating the clinical manifestations of dementing illnesses by improving the function of the remaining, but often metabolically compromised, cells.